Melatonin
Melatonin is a hormone made in the body, primarily released at night by the pineal gland in the brain. It acts like a neurotransmitter in regulating the sleep-wake cycle, and also plays roles in metabolic rate and immune function. Melatonin has been shown to exert protective effects on neurons, especially against oxidative stress, and may be protective against the development of various neurological diseases 1. As a dietary supplement, it is often used for the treatment of insomnia and jet lag, and may be relevant for the disordered sleep characteristic of MS2. Melatonin production decreases with age and in some neurological disorders, including MS3.
In an EAE animal model of MS, supplementation with melatonin at a dose of 1 mg/kg resulted in improved general condition (less weakness and paralysis) and antioxidant defenses, as well as reduced oxidative stress, inflammation, and bacterial dysbiosis4.
In a randomized, placebo-controlled clinical trial of MS patients (predominantly RRMS), melatonin at doses of 0.5-3 mg/day significantly improved mean total sleep time. There were statistical trends toward decreases in insomnia and post-sleep fatigue and improved sleep quality2.
In a clinical trial of all RRMS patients receiving disease-modifying therapies, melatonin at a higher dose of 5 mg/day reduced oxidant concentration and improved antioxidant activity and quality of life5. In a group of RRMS, PPMS, and SPMS patients also receiving disease-modifying therapies, the same dose resulted in a significant decrease in oxidant concentration and a fatigue score (used to evaluate chronic fatigue syndrome), including in comparison to mitoxantrone and interferon-beta6.
A high dose of 25 mg/day reduced levels of serum pro-inflammatory cytokines and oxidative stress markers in RRMS patients treated with interferon beta-1b, and was shown to be safe7. A lower dose of 3 mg/day was shown to be similarly effective in a mixed group of MS patients8.
Melatonin use during pregnancy is quite common, about 4% 9. There has been concern about using melatonin during pregnancy and breastfeeding due to findings in some animal research10,11, though this is inconsistent: other research has not only found no adverse effects from maternal melatonin administration, rather it showed evidence of being microbiome-protective12 and neuroprotective for offspring13,14, even normalizing impaired myelinization in animal models 15,16 (a related study in humans is currently under way17). More importantly, results from a review of 15 human studies (eight during pregnancy and seven during breastfeeding) suggested that melatonin up to 30 mg/day – much more than is generally marketed – during these periods is likely safe in humans9. Due to the scarcity of randomized placebo-controlled clinical trials, it is still recommended to discuss the matter with a healthcare professional prior to use.
Foods high in melatonin include tart cherries, goji berries, nuts, fish, eggs, and milk18.
References
1.Lee JG, Woo YS, Park SW, Seog DH, Seo MK, Bahk WM. The Neuroprotective Effects of Melatonin: Possible Role in the Pathophysiology of Neuropsychiatric Disease. Brain Sci. Oct 21 2019;9(10)doi:10.3390/brainsci9100285
2.Hsu WY, Anderson A, Rowles W, et al. Effects of melatonin on sleep disturbances in multiple sclerosis: A randomized, controlled pilot study. Mult Scler J Exp Transl Clin. Oct 2021;7(4):20552173211048756. doi:10.1177/20552173211048756
3.Hardeland R. Melatonin in aging and disease -multiple consequences of reduced secretion, options and limits of treatment. Aging Dis. Apr 2012;3(2):194-225.
4.Escribano BM, Munoz-Jurado A, Caballero-Villarraso J, et al. Protective effects of melatonin on changes occurring in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Mult Scler Relat Disord. Jan 11 2022;58:103520. doi:10.1016/j.msard.2022.103520
5.Adamczyk-Sowa M, Pierzchala K, Sowa P, Polaniak R, Kukla M, Hartel M. Influence of melatonin supplementation on serum antioxidative properties and impact of the quality of life in multiple sclerosis patients. J Physiol Pharmacol. Aug 2014;65(4):543-50.
6.Adamczyk-Sowa M, Sowa P, Adamczyk J, et al. Effect of melatonin supplementation on plasma lipid hydroperoxides, homocysteine concentration and chronic fatigue syndrome in multiple sclerosis patients treated with interferons-beta and mitoxantrone. J Physiol Pharmacol. Apr 2016;67(2):235-42.
7.Sanchez-Lopez AL, Ortiz GG, Pacheco-Moises FP, et al. Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis. Arch Med Res. Aug 2018;49(6):391-398. doi:10.1016/j.arcmed.2018.12.004
8.Yosefifard M, Vaezi G, Malekirad AA, Faraji F, Hojati V. A Randomized Control Trial Study to Determine the Effect of Melatonin on Serum Levels of IL-1beta and TNF-alpha in Patients with Multiple Sclerosis. Iran J Allergy Asthma Immunol. Nov 27 2019;18(6):649-654. doi:10.18502/ijaai.v18i6.2177
9.Vine T, Brown GM, Frey BN. Melatonin use during pregnancy and lactation: A scoping review of human studies. Braz J Psychiatry. May-Jun 2022;44(3):342-348. doi:10.1590/1516-4446-2021-2156
10.Gonzalez-Candia A, Veliz M, Araya C, et al. Potential adverse effects of antenatal melatonin as a treatment for intrauterine growth restriction: findings in pregnant sheep. Am J Obstet Gynecol. Aug 2016;215(2):245 e1-7. doi:10.1016/j.ajog.2016.02.040
11.Singh HJ, Keah LS, Kumar A, Sirajudeen KN. Adverse effects of melatonin on rat pups of Wistar-Kyoto dams receiving melatonin supplementation during pregnancy. Exp Toxicol Pathol. Nov 2012;64(7-8):751-2. doi:10.1016/j.etp.2011.01.011
12.Zhang H, Liu X, Zheng Y, et al. Effects of the maternal gut microbiome and gut-placental axis on melatonin efficacy in alleviating cadmium-induced fetal growth restriction. Ecotoxicol Environ Saf. Jun 1 2022;237:113550. doi:10.1016/j.ecoenv.2022.113550
13.Figueiro PW, Moreira DS, Dos Santos TM, et al. The neuroprotective role of melatonin in a gestational hypermethioninemia model. Int J Dev Neurosci. Nov 2019;78:198-209. doi:10.1016/j.ijdevneu.2019.08.004
14.Flinn T, McCarthy NL, Swinbourne AM, et al. Supplementing Merino ewes with melatonin during the last half of pregnancy improves tolerance of prolonged parturition and survival of second-born twin lambs. J Anim Sci. Dec 1 2020;98(12)doi:10.1093/jas/skaa372
15.Malhotra A, Rocha A, Yawno T, et al. Neuroprotective effects of maternal melatonin administration in early-onset placental insufficiency and fetal growth restriction. Pediatr Res. May 2024;95(6):1510-1518. doi:10.1038/s41390-024-03027-4
16.Miller SL, Yawno T, Alers NO, et al. Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction. J Pineal Res. Apr 2014;56(3):283-94. doi:10.1111/jpi.12121
17.Palmer KR, Mockler JC, Davies-Tuck ML, et al. Protect-me: a parallel-group, triple blinded, placebo-controlled randomised clinical trial protocol assessing antenatal maternal melatonin supplementation for fetal neuroprotection in early-onset fetal growth restriction. BMJ Open. Jun 22 2019;9(6):e028243. doi:10.1136/bmjopen-2018-028243
18.Pereira N, Naufel MF, Ribeiro EB, Tufik S, Hachul H. Influence of Dietary Sources of Melatonin on Sleep Quality: A Review. J Food Sci. Jan 2020;85(1):5-13. doi:10.1111/1750-3841.14952